Non insulin dependent diabetes mellitus (NIDDM or type II diabetes) is a major health problem which affects an estimated 17% of the American population. Although NIDDM in humans is highly heritable, its inheritance does not follow simple Mendelian laws and is, therefore, thought to be caused by the simultaneous action of many genes. Because such polygenic inheritance is still very difficult to unravel in humans, animal models offer significant advantages. We have recently identified the molecular basis for the recessive mouse mutation fat. This mutation confers the phenotype of adult onset obesity and hyperproinsulinemia. We have shown that the phenotype is caused by a missence mutation in the carboxypeptidase E (CPE) gene, leading to a virtual absence of CPE activity in neuroendocrine tissues. CPE is a processing enzyme involved in the maturation in a number of prohormones, among them proinsulin. During our work on cloning fat, we and others observed that the mutation is non-diabetogenic on the HRS inbred strain background, but leads to severe hyperglycemia in the strain BKS. This indicates that genes in BKS interact with fat to produce diabetes. We have preliminary evidence that this interaction is polygenic and that the contributing genes can be mapped in a F2 intercross between BKS-fat/fat and HRS-fat/fat. Here we propose to: map the diabetes susceptibility genes that interact with fat, and construct congenic strains that carry individual susceptibility genes. At the successful conclusion of this work, we will have determined the chromosomal location of the major diabetes susceptibility genes that interact with fat. Through examination of the congenic strains, we will determine what aspect of the diabetic phenotype these genes are controlling. In addition, we will lay the groundwork for an effort to positionally clone these genes to determine their molecular basis.